PROJECT SUMMARY Dyspnea is one of the most common and distressing symptoms associated with cancer, occurring in up to 70% of patients. The vast majority of patients with dyspnea experience frequent episodes of breathlessness triggered by daily activities, such as walking and bathing. Understandably, dyspnea with exertion can significantly limit patients' daily function and negatively impact their quality of life. If uncontrolled, these highly distressing dyspnea episodes can result in costly emergency room visits and hospitalizations. Because exertional dyspnea is under- researched, few effective treatment options are available. The long-term goal of our group's research is to develop effective, evidence-based therapies for dyspnea in patients with cancer. Exertional dyspnea is particularly difficult to treat because of its rapid onset, short duration, and high intensity. This raises the possibility that rapid-onset opioids that are currently approved for breakthrough cancer pain may be effective as prophylactic treatment to reduce exertional dyspnea and maximize function. On the basis of our preliminary data from recent clinical trials, we hypothesize that fentanyl sublingual spray (FSS) is effective in relieving exertional dyspnea. The overall objective of the proposed 3-arm, double-dummy, parallel- group randomized clinical trial is to compare the efficacy of FSS, morphine sulfate, and placebo in exertional dyspnea. The primary specific aim of this study is to compare the effect of prophylactic FSS, morphine sulfate, and placebo on the intensity of exertional dyspnea at the end of a shuttle walk test (SWT). In the second specific aim, we will compare their effects on SWT distance, average daily dyspnea, personalized daily activity, symptom burden, and quality of life. The third aim is to explore their effects on neurocognitive function, addictive potential, adverse effects, and pattern of opioid use. After obtaining written informed consent, we will monitor patients closely on usual opioids for 5 days before randomly assigning them to receive FSS, morphine sulfate, or placebo prophylactically once daily for 14 days. The proposed study is innovative in that the indications (i.e., exertional dyspnea and prophylactic management), intervention (i.e. FSS, proportionally dosed), patient population (i.e., patients with cancer), patient-reported outcome measures (e.g. personalized dyspnea activity, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events instrument, and Drug effects Questionnaire), and study design (i.e. home setting) that it will address are novel. The expected outcome of the proposed study is that FSS will be established as a treatment option for exertional dyspnea in patients with cancer while a rich dataset will be provided on the neurocognitive effects and addictive potential of opioids to inform safe opioid use during this era of opioid crisis. Successful completion of this adequately powered trial will have a positive effect on patient care by alleviating the intensity of exertional dyspnea, enhancing patients' ability to function in their daily lives, and improving the quality of life of these highly distressed patients.